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The structural and functional basis of chromosome synapsis and genetic exchange during mammalian meiosis


School of Biological Sciences

Dr O Davies , Dr M Wilson Wednesday, January 06, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

How is the chromosome number halved during meiosis to create haploid spermatozoa and oocytes that form healthy diploid zygotes upon fertilisation? At the heart of this process is the synaptonemal complex (SC), a zipper-like protein assembly that binds together homologous chromosome pairs and provides the necessary three-dimensional architecture for their exchange of genetic material through crossing-over prior to segregation. The supramolecular structure of the SC imposes a strict separation of 100 nm between homologous chromosomes, has a similar depth, and is continuous along the chromosome axis of up to 25 m, making it one of the largest individual protein structures in a cell. The SC is essential for meiosis, and its defects lead to human infertility, recurrent miscarriage and germline genetic disorders such as Down’s syndrome.

The human SC has eight known protein components (SYCP1-3, SYCE1-3, SIX6OS1 and TEX12), which perform distinct and critical roles in its molecular structure and function. We have previously determined how SYCP1 assembles into an SC-like lattice (Dunce et al 2018), SYCP3 forms a paracrystalline array that mediates chromatin looping and compaction (Syrjanen et al 2014) and how SYCE1 and SIX6OS1 undergo multivalent interactions that are disrupted in human infertility (Sánchez-Sáez et al 2020). However, it remains unknown how these distinct elements assemble together into the three-dimensional structure of the mature SC, which is essential to elucidating the molecular basis of its function in chromosome synapsis and crossover formation.

This project aims to uncover the molecular structure and assembly mechanism of the mammalian SC. We will determine the structure of SC proteins, assemblies and a biochemically-reconstituted SC through X-ray crystallography and Cryo-EM, alongside solution biophysics including light and X-ray scattering (MALS and SAXS). In parallel, we will study the structure of the native SC and SC-like polycomplexes through advanced EM imaging methods, including correlative light-electron microscopy and Cryo-EM tomography. Ultimately, this will allow us to dock high-resolution structures of SC components and assemblies into Cryo-EM maps of native and near-native full SC structures to achieve a full atomic model of the mammalian SC. This work will therefore provide training in a wide variety of advanced structural biology, biophysical and structural cell biology methods.

This PhD will form part of international collaborations in which our molecular findings will be tested in vivo through the generation and analysis of the meiotic phenotypes of mice harbouring structure-directed separation-of-function mutations. The outcome of this work will be an unprecedented mechanistic understanding of the molecular structure and assembly of the SC, and critically how its specific mutations lead to human infertility, recurrent miscarriage and aneuploidies.

This PhD project is based within Dr Owen Davies’ newly relocated lab that is funded by a £2m Wellcome Trust Senior Research Fellowship for the period 2021-2026.

The School of Biological Sciences is committed to Equality & Diversity: https://www.ed.ac.uk/biology/equality-and-diversity




Funding Notes

The “Institution Website” button on this page will take you to our Online Application checklist. Please complete each step and download the checklist which will provide a list of funding options and guide you through the application process.

If you would like us to consider you for one of our scholarships you must apply by 6 January 2021 at the latest.

References

Sánchez-Sáez, F., Gómez-H, L., Dunne, O.M., Gallego-Páramo, C., Felipe-Medina, N., Sánchez-Martín, M., Llano, E., Pendas, A.M. & Davies, O.R. (2020) Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility. Science Advances, 6 (36), eabb1660.
https://doi.org/10.1126/sciadv.abb1660

Dunce, J.M., Dunne, O.M., Ratcliff, M., Millan, C., Madgwick, S., Usόn, I. & Davies, O.R. (2018) Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nature Structural & Molecular Biology, 25, 557-569.
https://doi.org/10.1038/s41594-018-0078-9

Syrjanen, J.S., Pellegrini, L. & Davies, O.R. (2014) A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife, 3, e02963.
https://doi.org/10.7554/eLife.02963

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